Loss of CNFY toxin-induced inflammation drives Yersinia pseudotuberculosis into persistency

Abstract

Gastrointestinal infections caused by enteric yersiniae can become persistent and complicated by relapsing enteritis and severe autoimmune disorders. To establish a persistent infection, the bacteria have to cope with hostile surroundings when they transmigrate through the intestinal epithelium and colonize underlying gut-associated lymphatic tissues. How the bacteria gain a foothold in the face of host immune responses is poorly understood. Here, we show that the CNFY toxin, which enhances translocation of the antiphagocytic Yop effectors, induces inflammatory responses. This results in extensive tissue destruction, alteration of the intestinal microbiota and bacterial clearance. Suppression of CNFY function, however, increases interferon-γ-mediated responses, comprising non-inflammatory antimicrobial activities and tolerogenesis. This process is accompanied by a preterm reprogramming of the pathogen's transcriptional response towards persistence, which gives the bacteria a fitness edge against host responses and facilitates establishment of a commensal-type life style.

Yersinia pseudotuberculosisExploits CD209 Receptors for Promoting Host Dissemination and Infection

“…Second, they discovered that Yersinia germs can also reduce the production of toxins that induce the inflammation of the afflicted tissues during infection. Therefore, the reduction of inflammation allows bacteria to escape attacks from the host immune system (53). This process is now named "bacteria persist as stowaways" (https://health.economictimes.indiatimes.com/news/ industry/bacteria-persist-as-stowaways-hzi/62836896).…”

Crystal structure of full-length cytotoxic necrotizing factor CNFYreveals molecular building blocks for intoxication

“…Many bacterial exotoxins are key virulence factors which target different functions of host cells to break barriers, improve excess to nutrients, defeat immune responses and promote bacterial dissemination to colonize, proliferate, persist and spread within and among hosts. Some of these toxins, including the family of cytotoxic necrotizing factors (CNFs), were shown to modulate the expression of inflammatory mediators that orchestrate innate immune responses and promote tissue damage, leading to the development of acute disease symptoms (Knust & Schmidt, 2010;Schweer et al, 2013;Diabate et al, 2015;Cavaillon, 2018;Heine et al, 2018).…”

“…Moreover, CNF1 was recently shown to favor malignant tumor conversion and invasiveness by inducing epithelial to mesenchymal transition in intestinal epithelial cells as well as to provoke reversible senescence of human colon cancer cells (Zhang et al, 2018;Fabbri et al, 2019). Similarly, the homologous toxin CNF Y , which shares 65% identity with E. coli CNF1, is crucial for the pathogenicity of Yersinia pseudotuberculosis, which causes food-borne and zoonotic enteric infections that manifest themselves as enteritis, mesenterial lymphadenitis and more rarely, in sequelae such as reactive arthritis (Koornhof et al, 1999a;Smego et al, 1999;Heine et al, 2018). The importance of CNF Y is emphasized by the fact that a knockout mutation of the cnfY gene leads to avirulence, allowing bacteria to become persistent in mice (Heine et al, 2018).…”

“…Similarly, the homologous toxin CNF Y , which shares 65% identity with E. coli CNF1, is crucial for the pathogenicity of Yersinia pseudotuberculosis, which causes food-borne and zoonotic enteric infections that manifest themselves as enteritis, mesenterial lymphadenitis and more rarely, in sequelae such as reactive arthritis (Koornhof et al, 1999a;Smego et al, 1999;Heine et al, 2018). The importance of CNF Y is emphasized by the fact that a knockout mutation of the cnfY gene leads to avirulence, allowing bacteria to become persistent in mice (Heine et al, 2018). Recent studies demonstrated that Rho-GTPase activation by CNF Y enhances the translocation of Yersinia outer proteins (Yops) into neutrophils and macrophages via a type III secretion system (T3SS).…”

RNA Atlas of Human Bacterial Pathogens Uncovers Stress Dynamics Linked to Infection

“…These responses, commonly called stress responses, are critical for pathogen invasiveness and protection from host immunity, which makes them topics of interest for future development of new antimicrobials. The responses are often complex, and synergistic regulation of regulatory networks can be pivotal in sensing and adapting to environments in different colonization niches during different phases of infection (Avican et al, 2015;Heine et al, 2018;Malachowa et al, 2015;Mandlik et al, 2011;Nuss et al, 2017). Infecting bacteria encounter numerous stress conditions which vary depending on the route and phase of infection.…”